Treatment for Panic Attack

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Benzodiazepines Benzodiazepines taken alone cause drowsiness, ataxia, dysarthria, nystagmus, and occasionally respiratory depression, and coma. Activated charcoal can be given within 1 hour of ingesting a significant quantity of benzodiazepine, provided the patient is awake and the airway is protected. Benzodiaz-epines potentiate the effects of other central nervous system depressants taken concomitantly. Use of the benzodiazepine antagonist flumazenil unlicensed indication can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodia-zepine-dependent patients. Flumazenil may prevent the need for ventilation, particularly in patients with severe respiratory disorders it should be used on expert advice only and not as a diagnostic test in patients with a reduced level of consciousness.

Major affective and anxiety disorders represent the most common psychiatric illnesses and are those encountered most often by primary-care clinicians. Major depression may represent a spectrum of disorders, varying in severity from mild and self-limited conditions to extraordinarily severe, psychotic, incapacitating, and deadly diseases. The antipsychotic, antianxiety, antimanic, and antidepressant drugs affect cortical, limbic, hypothalamic, and brainstem mechanisms that are of fundamental importance in the regulation of arousal, consciousness, affect, and autonomic functions. Physiological and pharmacological modifications of these brain regions may have important behavioral consequences and useful clinical effects regardless of the underlying cause of any mental disorder. The lack of diagnostic or even syndromal specificity of most psychotropic drugs tends to reduce the chances of finding a discrete mechanistic correlate for a specific disease based simply on the actions of...

The primary clinical manifestations of major depression are significant depression of mood and impairment of function. Some features of depressive disorders overlap those of the anxiety disorders, including panic-agoraphobia syndrome, severe phobias, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Extremes of mood also may be associated with psychosis, as manifested by disordered or delusional thinking and perceptions that often are congruent with the predominant mood. Conversely, secondary changes in mood may be associated with psychotic disorders. This overlap of disorders can lead to errors in diagnosis and suboptimal treatment. Mood and anxiety disorders are the most common mental illnesses, each affecting up to 10 of the general population at some time in their lives. Anxiety disorders may be acute and transient, or more commonly, recurrent or persistent. Symptoms may include mood changes (fear, panic, or...

Anxiety is a symptom of many psychiatric disorders and an almost inevitable component of many medical and surgical conditions. Symptoms of anxiety commonly are associated with depression and especially with dysthymic disorder (chronic depression of moderate severity), panic disorder, agoraphobia and other specific phobias, obsessive-compulsive disorder, eating disorders, and many personality disorders. Sometimes, no treatable primary illness is found, or if one is found and treated, it may be desirable to deal directly with the anxiety at the same time. In such situations, antianxiety medications are frequently and appropriately used. Currently, the benzodiazepines and the SSRIs are the most commonly employed pharma-cotherapies for common clinical anxiety disorders (see Chapter 16). Benzodiazepines sometimes are given to patients presenting with anxiety mixed with symptoms of depression, although their efficacy in altering the core features of severe major depression has not been...

There is insufficient evidence for meaningful analgesic properties of benzodiazepines in most clinical circumstances (Reddy and Patt 1994). Benzodiazepines have been employed acutely to mitigate pain arising from muscle spasm, e.g., after spinal cord injury. This effect may be due to an indirect effect related to their psychotropic properties, i.e., alleviation of anxiety. The presumption is that reducing patient anxiety attenuates muscle tension and associated musculoskeletal pain. Other uses for benzodiazepines have included treatment of restless legs syndrome, tension headache, and neuropathy (Bartusch et al. 1996, Bouckoms and Litman 1985, Dellemijn and Fields 1994). Clonazepam and alprazolam might be effective in patients with lancinating neuropathic pain in which allodynia is a prominent feature (Reddy and Patt 1994, Bouckoms and Litman 1985). Long-term benzodiazepine use among patients with chronic pain is controversial. Benzodiazepines are gamma-aminobutyric acid (GABA)...

Biological target 3-Substituted 1,4-benzodiazepine-2-one (1,4-BZD) molecules are privileged structures, in that minor changes can produce a wide variety of biological actions. 1,4-BZD drugs have been developed that target a variety of biological ligands. Here, four exemplary 3-amino substituted structures are discussed, three of which inhibit g-secretase, an enzyme that cleaves amyloid precursor protein (APP) to form amyloid-p-peptide (Ap) deposits in the brain of Alzheimer's patients. The fourth, 1,4-BZD, L-768,673, is a potassium channel inhibitor that delays the initiation of the cardiac action potential.

Alprazolam, (Xanax), is rapidly absorbed from the GI tract. Protein binding is lower ( 70 ) than with most benzodiazepines because of its lower lipophilicity. a-Hydroxylation of the methyl group to the methyl alcohol (a reaction analogous to benzylic hy-droxylation) followed by conjugation is rapid consequently, the duration of action is short. The drug is a highly potent anxiolytic on a milligram basis. Triazolam, USP. Triazolam, benzodiazepine (Halcion), has all of the characteristic benzodiazepine pharmacological actions. It is an ultra-short-acting hypnotic because it is rapidly a-hydroxylated to the 1-methyl alcohol, which is then rapidly conjugated and excreted. Consequently, it has gained popularity as sleep inducers, especially in elderly patients, because it causes less daytime sedation. It is metabolically inactivated primarily by hepatic and intestinal CYP3A4 therefore, coadministration with grapefruit juice increases its peak plasma concentration by 30 ,...

Generally speaking, drugs of the benzodiazepine group have been viewed with caution in long-term pain management because of the increasingly recognized problems of tolerance and dependence. However, although under most circumstances they are not analgesic, they are anxiolytic and, to varying degrees, antispastic. This last property may be valuable in the treatment of pain associated with muscular hypertonia. Spasticity may be relieved by both benzodiazepines and baclofen. Dan-trolene, which acts peripherally on striated muscle, is of dubious value as a sole antispastic agent but may act synergistically with baclofen.14 Baclofen has an anti-nociceptive action distinct from its antispastic effect, but the clinical effect in most pain associated with neurologic disease is probably marginal when it is given systemically (see below under Spinal drug administration).

Summary This journal article discusses issues in the treatment of depression, anxiety, and sleep disturbances in patients with dementia. The author reviews evidence suggesting that both pharmacologic and nonpharmacologic therapies are effective for the treatment of depression, and that treatment for depression in dementia should focus not only on symptomatic relief but also on functional improvement. He notes that little attention has been given to the treatment of anxiety in patients with dementia, and advises that benzodiazepines should be used with caution in such patients because of the risk of worsening their cognitive function. He also discusses considerations in the effective management of sleep disturbance in patients with dementia, including the use of nonpharmacologic approaches such as activity programs, environmental interventions, and educational interventions.

Childhood-onset obsessive-compulsive disorder Pediat-ric-onset obsessive-compulsive disorder Obsessive-Compulsive Disorder (OCD) is currently classified as an anxiety disorder ( Anxiety Disorders) in Compulsions are repetitive physical or mental acts an individual feels driven to perform in a characteristic, stereotyped way, usually to relieve the anxiety or discomfort associated with depression. Typical symptoms of OCD include contamination obsessions and cleaning compulsions (i.e., fear of germs and compulsive hand washing), forbidden thoughts (i.e., obsessions about harm coming to self or others, sexual, or religious obsessions), hoarding, and symmetry (i.e., the need to have things symmetrical, ordered, arranged) (Bloch et al. 2008). These obsessions and or compulsions must be severe enough to cause significant distress or impairment or be time-consuming (take up more than 1 h a day). Typically, patients with OCD have insight that their obsessions and compulsions are excessive and...

This disorder is characterized by recurrent unexpected panic attacks followed by at least 1 month of persistent concerns about additional attacks (i.e., anticipatory anxiety), worry about the implications or consequences of the panic attack or significant changes in behavior (e.g., avoidance) related to the attacks. Panic attacks are not better accounted for by a comorbid mental disorder and are not normally due to the direct physiological effects ofa substance or general medical condition. Depending on whether criteria are also met for agoraphobia, panic disorder with or without agoraphobia is diagnosed.

Positive modulators at GABAa receptors enhance 3H benzodiazepine binding, which has been widely used as a marker for GABAa receptor activation. Anesthetic drugs, such as pentobarbital, exert dual actions at the benzodiazepine receptors they augment the action of GABA, and in the absence of GABA, they directly increase channel opening.47 The ability of agents to enhance benzodiazepine binding in the absence of GABA is also termed the direct action, and the enhancement in the absence of GABA is sometimes referred to as the indirect or augmentative action. A similar phenomenon is observed in electrophysiologic studies. Which of these actions is responsible for the pharmacologically relevant actions of anesthetics is unknown. However, augmentation of GABA actions generally is observed at lower concentrations than is direct gating of the channel. In addition, a number of agents, such as phenobarbital and benzodiazepine, which are not efficacious anesthetics, lack direct actions in...

Government supports a variety of research studies relating to benzodiazepines. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to benzodiazepines. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore benzodiazepines. The following is typical of the type of information found when searching the CRISP database for benzodiazepines

Summary (Applicant's Abstract) Research in baboons is proposed to characterize the intravenous reinforcing and physical dependence-producing effects of benzodiazepines and also to examine caffeine reinforcement interactions with cocaine and nicotine. Two self-injection studies will determine whether physical dependence enhances the reinforcing effects of a benzodiazepine. A series of three studies will address concerns that the abuse liability of benzodiazepines is enhanced by interactions with opioids by determining whether chronic opioid exposure increases benzodiazepine self-injection and whether the discriminative stimulus effects of benzodiazepines and opioids mutually potentiate each other. One study will determine whether the abuse liability of sedative drugs can be reduced by slowing the rate of drug onset. A final self-injection study will explore the concern that flunitrazepam has a particularly high abuse liability. A second series of studies will examine benzodiazepine...

Several studies have established the efficacy of sertraline in the treatment of social anxiety disorder (also known as social phobia). In one of the earliest studies, sertraline treatment (at flexible doses of 50-100 mg day) showed a statistically significant improvement compared with placebo, as measured by the Liebowitz Social Anxiety Scale (LSAS) (Katzelnick et al. 1995). A large double-blind, placebo-controlled study followed more than 200 Canadian outpatients with generalized social phobia for 20 weeks, measuring response on CGI-I scores and mean reductions on the social phobia subscale of the Marks Fear Questionnaire and the Brief Social Phobia scale (Van Ameringen et al. 2001). Fifty-three percent of patients treated with sertraline, compared with only 29 of patients receiving placebo, were either much or very much improved by the study's end, as measured by CGI-I scores. Statistically significant changes favoring sertraline were seen on the other two study measures as well....

Summary The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic anti-anxiety, and sedative hypnotic aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in...

Anxiety disorders have recently been found to be correlated more closely than depression with chronic painful conditions in a large US sample of chronic pain patients.26 In particular, people who are fearful of anxiety-related sensations, who interpret somatic symptoms as harmful and who avoid situations where these feelings are likely to arise, have greater disability.27 The term anxiety sensitivity'' has been used to describe this condition in these individuals.28 The diagnoses included under this rubric comprise generalized anxiety disorder (GAD), panic disorder, phobias, posttraumatic stress disorder, adjustment disorders, and obsessive compulsive disorder.

The symptoms of this disorder include excessive anxiety and worry, occurring frequently for a period of at least six months with difficulty in controlling this. Additionally, the person concerned has at least three additional symptoms including restlessness, becoming tired easily, difficulty in concentrating, irritability, muscle tension, or disturbed sleep.29 Early work suggested that female patients with chronic pain and who were not seeking compensation had a higher frequency of GAD than expected,30 although women with anxiety were not found to have a poorer prognosis compared with men in a recent investigation.31 Higher degrees of anxiety were related to greater intensity of pain in this study.31 This same study showed that patients with this symptom have a poorer prognosis and this has been shown by others.32 It has been suggested that patients with chronic pain may use worry to reduce the physical sensations associated with pain, and thus fulfil the diagnostic criteria for...

Recent studies have begun to confirm the widely held hypothesis that caffeine can be a contributing factor in the maintenance, and perhaps even genesis, of some anxiety disorders. Included are post-traumatic stress disorder (PTSD),223 phobia,304,305 obsessive-compulsive disorder,306 and panic dis-order.307-309 One study showed, for example, that excessive caffeine consumption is a common factor in the PTSD reactions seen in combat troops. Based on their results, the investigators recommended decaffeinated beverages for all troops entering combat situations.223 There is also an emerging body of research that implicates caffeine in the genesis of panic attacks,309,310 and the drug has long been used as a panicogenic agent to elicit anxious reactions for clinical purposes.307308 One study recently showed that caffeine can cause the dysregulation of multiple neuronal systems that results in panic attacks.308 Moreover, this panic response to excessive amounts of caffeine was found to have...

Summary Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine...

The 5-HT2 receptor family seems to be particularly involved in anxiety because several drugs effective for the treatment of anxiety disorders interact with this type of receptor (Mora et al. 1997 Peroutka 1995). Mora et al. (1997) tested mCPP, ritanserin and propen-1-yl phenol hemifumarate (SR-463496A), a selective 5-HT2A 2C receptor antagonist (Rinaldi-Carmona et al. 1992) on two types of fear. The authors used a paradigm in which the same rat in one experimental session was exposed to two types of fear, in an elevated T-maze with the perpendicular arm closed and the other with arms open. By placing the animal in the closed arm, the training of inhibitory passive avoidance is evaluated by measurement of the time that the animal takes to leave the closed arm during three consecutive trials. This inhibitory avoidance task is assumed to represent conditioned fear. The same animal is placed in the open arm in a one-way escape task, which is assumed to represent unconditioned fear (Graeff...

The question arises whether anxiolytic activity must always be accompanied by concomitant skeletal muscle relaxant and anticonvulsant activity as well as strong sedation. Can an anxioselective drug exist that will not interact significantly and additively with CNS depressant compounds, particularly alcohol More significantly, both from a medical and sociologic viewpoint, will it be possible to treat anxiety and stress without the added complication of potent sedative effects, dependency, and abuse Evaluation of a series of cyclic imides as potential psychotropic agents yielded three candidates with tranquilizing action and very low sedative effects. The compound chosen for detailed pharmacologic evaluation, MJ9022-1, buspirone (BS), was marketed in 1986 as the first member of a new class of azaspirodecanediones. Early screening led to the erroneous belief that the compound might have antipsychotic properties. However, when further testing revealed that the compound had a taming effect...

Although the brain is undoubtedly the most wondrously complex organ, it is possible to distil the way it works into two opposing forces excitation and inhibition (depressing). Central nervous system (CNS) depressants are drugs that can be used to slow down or depress the functions of the CNS. Although many agents have the capacity to depress the function of the CNS, CNS depressants discussed in this chapter include only anxiolytics, sedative-hypnotics, and antipsychotics. There is some overlap between the first two groups. They often have several structural features in common and likewise often share at least one mode of action, positive modulation of the action of y-aminobutyric acid (GABA) at GABAa receptor complex. The list of anxiolytic, sedative, and hypnotic drugs is a short one benzodiazepines, Z-drugs, barbiturates, and a miscellaneous group. Antipsychotic drugs previously known as neuroleptic drugs, antischizophrenic drugs, or major tranquilizers are used in the symptomatic...

Benzodiazepines are widely used for the treatment of anxiety and insomnia as well as a variety of other disorders. In most countries they are available on medical prescription. Problems of dependence and abuse have been recognized for some time, although the dependence potential of these drugs remains a matter of contention.14 In addition to their anxiolytic and hypnotic effects, benzodiazepines produce sedation, muscle relaxation, and cognitive and psychomotor impairment. This antagonistic relationship may hold for certain behavioral effects only. De Angelis et al.19 found that the effects of caffeine were reversed by desmeth-yldiazepam and chlor-desmethyldiazepam in the hole-board and spontaneous motor activity tests in mice. In contrast, benzodiazepine coadministration enhanced the increase in open-field exploratory behavior induced by caffeine. It should be noted that in this latter test some benzodiazepine doses produced increased exploratory activity when administered alone....

The Spielberger State-Trait Anxiety Inventory (STAI)28 is the most widely used measure of anxiety, a construct that is not used as extensively as depression is with chronic pain patients, but nevertheless a very important one with pain patients. The STAI is a 40-item inventory that assesses trait anxiety, a characterological, stable dimension of anxiety that is relatively consistent over time, as well as state anxiety, transitory feelings of anxiety usually in response to specific situations. Patients are asked to rate statements on a four-point scale regarding how they feel right now (state anxiety) and how they feel generally (trait anxiety).

Benzodiazepines have been employed acutely to mitigate pain arising from muscle spasm (e.g., after spinal cord injury). The presumption is that patients with marked anxiety are prone to heightened muscle tension, which may exacerbate musculoskeletal pain. Other uses for benzodiazepines have included treatment of restless legs syndrome, tension headache, and neuropathy (Bartusch et al. 1996 Bouckoms and Litman 1985 Dellemijn and Fields 1994). Clonazepam, a long-acting benzodiazepine, might be effective in patients with neuropathic pain in which allodynia (painful sensations elicited by normally nonnoxious stimuli, such as a bedsheet pulled up along the legs) appears to be a prominent feature (Bouckoms and Litman 1985). Protracted benzodiazepine use among patients with chronic pain is controversial in that benzodiazepines are GABA agonists and as such may influence 5-HT neurotransmitter release, attenuating opioid analgesia (Nemmani and Mogil 2003), with the potential for increasing...

The treatment of anxiety and sleep disorders is dominated by the BZDs. These drugs induce sleep (act as hypnotics) in high doses and lead to sedation and reduced anxiety (anxiolytic) at lower doses. They function by an enhancement of the GABA-mediated inhibition of the CNS and act in an allosteric manner on the GABA receptor. The discovery of the A number of animal screens for tranquilizers involving relaxing muscle in the cat and foot shock tests on mice were available in the 1950s. Today such screening tests would be replaced by receptor and enzyme screens. In 1955, a series of quinazoline derivatives were being examined. Treatment of the quinazoline N-oxide 4.73 with methylamine gave an unknown compound, which was not tested until the project was coming to an end in May 1957. The compound showed activity comparable to the well-known tranquilizers phenobarbital and chlorproma-zine. Chemical studies then established the structure as a benzodiazepine 4.74. The patent was filed in May...

A large body of evidence from family, twin, and adoptee studies has been accumulated that a complex genetic component is involved in anxiety-related traits and in the liability to anxiety spectrum disorders. While genetic research has typically focused either on normal personality characteristics or on psychiatric disorders, with few investigations evaluating the genetic and environmental relationship between the two, it is of critical importance to answer the questions whether a certain quantitative trait etiopathogenetically influences the disorder or whether the trait is a syndromal dimension of the disorder. Nevertheless, some studies have implicated anxiety-related personality traits, such as neuroticism or negative emotionality, in the comorbidity of mood disorders (Kendler et al. 1993a Livesley et al. 1998). Separation of anxiety spectrum disorders from mood disorders including depression and bipolar disorder in current consensual diagnostic systems remarkably enhanced interest...

While multiple lines of evidence implicate the serotonin 1A receptor (5HT1A) in the pathophysiology of anxiety and depression as well as in the mechanism of action of anxiolytics antidepressants, its relevance to the therapeutic effectiveness of these drugs has been a matter of considerable debate (Griebel 1995 Hensler 2003 Hjorth et al. 2000 Lesch et al. 2003). The 5HT1A receptor is encoded by an intronless gene (HTR1A) located on human chromosome 5q12.3. Several rare missense polymorphisms, including the Gly22Ser variant which results in altered agonist-elicited downregulation, have been found within the protein coding of HTR1A. Moreover, Lemonde and coworkers (Lemonde et al. 2003) reported a functional C-1019G single nucleotide polymorphism (SNP) in the transcriptional control region of HTR1A (HTR1A-1019) and demonstrated in in vitro experiments that the G variant displays differential binding efficiency of the repressors enhancer-type transcriptional regulator NUDR DEAF-1. NUDR...

The most recently proposed mechanism of action of caffeine is through its interaction with benzodiazepine binding sites. This mechanism was suggested because caffeine antagonizes or modifies the effects of benzodiazepines on both animal and human behavior.14 However, caffeine is a much more potent antagonist of adenosine than it is of benzodiazepine receptor, and the inhibition of benzodiazepines may even be mediated by adenosine receptors. Further, like the first two mentioned mechanisms, the inhibition of benzodiazepine receptors occurs only at toxic plasma levels of caffeine.15

Caffeine at 5 to 40 mg kg IP or 600 mg kg in food has been shown to increase,65-67 decrease,68 or cause no change34,69 in the number of benzodiazepine receptors in the brain. Moreover, caffeine increases the binding of benzodiazepines to their receptor site in vivo,70,71 but decreases binding in cultured neurons.72 However, the number of benzodiazepine receptors is affected by stress, and different types of stress can either increase or decrease benzodiazepine receptor density. Also, the addition of caffeine to the diet did not affect benzodiazepine receptor density, while daily administration of caffeine by the intraperitoneal route, which is stressful, did.73 74 Therefore, the evidence that there is a direct affect by caffeine on benzodiazepine receptors is relatively weak. Finally, the concentrations of caffeine needed to antagonize benzodiazepine receptors is five to ten times higher than those needed to antagonize adenosine receptors.75 76 This may explain the lack of effect with...

Anxiety disorders (GAD, specific phobias, panic disorder, social anxiety disorder) Adjustment disorders and chronic, e.g., dementia) Anxiety in depression (as an adjunct at initiation of anti- Suicidal patients with prominent anxiety symptoms Intolerance of SSRIs SNRIs is another important reason to prescribe benzodiazepines. SSRIs SNRIs sometimes cause a paradoxical increase in anxiety at initiation of treatment that calls for adjunct prescribing of a BZ. Although anxiety is not a DSM-Iv criterion for a major depressive episode, clinicians should be aware of the frequent anxiety component in depression that needs to be addressed, as anxiety may precipitate suicidal acts. BZ anxiolytics are recommended for short-term (&lt 1 month) relief of anxiety and insomnia and as an adjunct Another guideline emanating from the Psychophar-macology Unit at the University of Bristol in 1995 advises that patients with panic, generalized, or social anxiety disorder be started on an SSRI SNRI and given...

There is much speculation as to how anxiety can influence pain. For example, pain can heighten anxiety, which in turn can result in muscle strain and spasm. If the strain and spasm are severe enough, localized ischemia and muscle cell damage can arise, resulting in the release of pain-producing substances that then precipitate further pain. Heightened responses of lower back muscles, as shown by electromyography (EMG), were observed among patients discussing personal anxiety-provoking stressors (Flor et al. 1985). Similarly, heightened tension in frontal muscles, associated with personal distress, was noted among patients with tension headaches. This anxiety-pain relationship makes intuitive sense but has not been consistently borne out in evaluations using EMG. One reason for this is that although EMG can reflect activity in superficial muscles, it may not measure the recordings of deeper muscles, where pain may actually originate. Also, a time lag is expected between the experience...

The HPA axis has also been studied in patients with anxiety disorders, particularly panic disorder, with and without comorbid major depression. Both the cortisol response to dexamethasone and the response to CRH have been examined in pure panic disorder without comorbid depression. The earliest study with dexamethasone demonstrated a 15 nonsuppression rate in panic disorder (Curtis et al. 1982). A number of other studies have since been conducted, and the overall incidence of cortisol nonsuppression is 17 in panic disorder (13 studies), while the incidence for major depression is 50 (Heninger 1990). Grunhaus et al. (1987) compared patients with major depression to those with major depression with panic disorder and found a similar rate of cortisol nonsuppression following dexamethasone administration (approximately 50 ) in the two populations, suggesting that the presence of comorbid panic disorder had little impact beyond that of depression on dexamethasone nonsuppression. In CRH...

Clonazepam is recognized as a treatment for epilepsy and in particular status epilepticus where it is given as an IV infusion. In addition to its anticonvulsant properties, clonazepam has several other potentially useful properties. Clonazepam can reduce muscle spasm, induce sleep, and reduce neuropathic pain with an impression that it is most effective for lancinating pain. In addition, it has amnesic and anti-anxiety effects. One would expect that with its long half-life that if taken on a regular basis, even if only at night, the day-time sedation would complicate its use. In practice, while such sedation may occur, it is not universal. Clonazepam, 05-1.5 mg, at night can be useful as an aid to sleep, particularly in patients where muscle spasm or lancinating pain is problematical and where the patient is of an anxious disposition. Its hypnotic effects make it an alternative to a tricyclic antidepressant which is often used to improve sleep. Case reports also suggest that...

Mogadon Nitrazepam is an anxiolytic drug of the benzodiazepine class. It is a nitrobenzodiazepine and like other benzodiazepines, in addition to its anxiolytic properties, it is a hypnotic drug with sedative, amnestic, anticonvulsant, and muscle-relaxant effects. It is long-acting, lipophilic, and is metabolized in the liver by oxidation. It acts as a full agonist at benzodiazepine receptors in the brain, enhancing binding of ligands for GABAa receptors. It has Benzodiazepines Sedative, Hypnotic, and Anxiolytic Dependence Social Anxiety Disorder

None of the tricyclic or tetracyclic drugs are approved for use in panic disorder. Yet imipramine was the first drug described for use in this disorder (Klein 1964). In fact, observation of the effects of imipramine helped to establish the diagnostic utility of panic disorder. The efficacy of both tertiary and secondary tricyclics has been demonstrated in controlled trials (Jobson et al. 1978 Munjack et al. 1988 Zitrin et al. 1980). In treating this disorder, the drug is initiated at a low dose to avoid exacerbation of panic symptoms.

Conflicting data exist concerning the efficacy of buspirone augmentation. Many open trials have suggested efficacy as an augmentation strategy (302-305) however, placebo-controlled trials have not fully supported the clinical reports. In a study of 102 outpatients with MDD who did not have an adequate response to 6 weeks of treatment with fluoxetine or citalopram, buspirone (doses of 10-30 mg b.i.d.) or placebo was added after a 2-week placebo wash-in period (306). Although buspirone was superior to placebo on the MADRS after 1 week, no difference was found at 6 weeks, except in patients with baseline MADRS scores greater than 30. In another study of 119 patients who failed to respond to paroxetine or placebo after a minimum of 4 weeks, buspirone or placebo was added for an additional 4 weeks (307). Although the combinations were well tolerated, there was no difference between groups, with both showing substantial improvement on the Clinical Global Impression Scale (50.9 buspirone,...

Anxiety is a very common concomitant condition in patients with chronic pain, presenting as panic, PTSD, obsessive compulsive disorder (OCD), etc. Although anxiolytics do not possess intrinsic analgesic activity, anxiety is often accompanied by somatic complaints of chest pain, GI upset, or neurologic symptoms such as dysesthesias, headache, which may be relieved by anxiolysis. Benzodiazepines are also a mainstay in the treatment of restless legs syndrome (RLS). Although most RLS studies were conducted with clonazepam, current recommendations focus on shorter acting benzodiazepines such as triazolam (Silber et al. 2004).

The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and benzodiazepines, you will need to use the advanced search options. First, go to http chid.nih.gov index.html. From there, select the Detailed Search option (or go directly to that page with the following hyperlink The trick in extracting studies is found in the drop boxes at the bottom of the search page where You may refine your search by. Select the dates and language you prefer, and the format option Journal Article. At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display whole records. We recommend that you type benzodiazepines (or synonyms) into the For these words box. Consider using the option anywhere in record to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this...

Summary Flexible sigmoidoscopy remains a common tool used for the periodic screening of colorectal cancer. This article reminds family care physicians of the recommendations for the use of flexible sigmoidoscopy. Most organizations recommend screening at three to five year intervals beginning at age 50 for persons with average risk. Extensive training in endoscopic maneuvering, colorectal anatomy, and pathologic recognition is required. Most physicians report comfort performing the procedure unsupervised after 10 to 25 supervised sessions. The procedure itself involves the insertion of the sigmoidoscope through the anus and distal rectum and advancement of the scope tip to an average depth of 48 to 55 centimeters in the sigmoid colon. Once the sigmoidoscope has been appropriately advanced, the scope is slowly withdrawn, allowing for the inspection of colon mucosa during withdrawal. Polyps less than 5 millimeters in diameter should be biopsied. Polyps 5 to 10 millimeters or greater can...

Summary In this article, the author provides readers with information about an often-encountered, but little-discussed complication of dialysis, insomnia. Topics include the adequacy of dialysis and its impact on the sleep habits of patients restless leg syndrome (RLS) and the role of peripheral neuropathy in its development the use of Sinemet to treat RLS using conventional sleep aids, including Ambien the use of muscle relaxants, or benzodiazepines, for milder forms of RLS psychological sleep disturbances and adjunctive therapies, including Qigong, biofeedback, and meditation. The author encourages readers to become more self-aware and to participate as an active member of their own health care team. The article includes a short list of references and organizations that may provide additional information about sleep disorders and their therapy.

Summary Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. This article explores the role of the primary care physician in the diagnosis and management of RLS. Patients with RLS have an irresistible urge to move their legs, usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. The authors estimate that between 2 and 15 percent of the population may experience symptoms of RLS. Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions, pregnancy, and uremia (urea in the blood). RLS also may occur secondarily to certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions to assess the likelihood of RLS is included in the article. Drug therapy includes dopaminergic agents, opioids, benzodiazepines, and anticonvulsants. The primary care physician can incorporate sleep and...

Summary Some institutionalized elderly persons need a sedative prior to a dental examination or treatment because they have a disturbance due to physical illnesses, degenerative changes in the brain, or psychiatric disorders, associated with advanced aging. Oral administration is one of the safest methods of delivery of a sedative drug. It is almost universally acceptable, easy to administer, costs little, has a low incidence and severity of adverse reactions, and requires no additional formal specialized training for the dentist. However, theoretical and practical knowledge of sedation is essential. This article reviews the literature on oral sedation for the geriatric patient. Benzodiazepines are most often used for oral sedation of geriatric patients. The properties of these drugs are reviewed, and recommendations are made with respect to the drugs of choice and their dosage. Generally, fast acting benzodiazepines of short duration, with rapid rate of elimination and no active...

Pharmacological, that can help control these behaviors. Non-pharmacological treatment options include environmental changes, bright-light treatment, and restraints and behavior modification. Pharmacological options involve the use of neuroleptics, benzodiazepines, and other agents such as beta-blocker therapy, carbamazepine, lithium, trazodone hydrochloride, and buspirone hydrochloride. According to the authors, patients should be assessed to differentiate delirium from dementia, and possible precipitants of disturbed behavior should be investigated. The authors suggest that ultimately, long-term success with patients with dementia may depend in part on realistic expectations. 21 references.

Summary This article describes Alzheimer's disease as an increasingly common management concern for primary care physicians. Although little can be done for the primary symptoms of the dementing process, the secondary behavioral complications of this illness may be amenable to behavioral or pharmacologic manipulation. Agitation may be responsive to environmental or psychosocial intervention. Treatment with low doses of antidepressants can improve depressive symptoms. Mild anxiety is best treated with emotional support from the family and caregiver. Benzodiazepines can be used with caution. Insomnia can be reduced by encouraging a routine that prevents daytime napping and keeping the patient busy during the day. Pharmacotherapy for disturbed sleep often causes more harm than good and should be avoided if possible. 3 references. (AA-M).

Summary This article discusses burning mouth syndrome (BMS), a condition that is characterized by a burning sensation in the tongue or other oral sites, usually in the absence of clinical and laboratory findings. Affected patients often present with multiple oral complaints, including burning, dryness, and taste alterations. Burning mouth complaints are reported more often in women, especially after menopause. Typically, patients awaken without pain but note increasing symptoms through the day and into the evening. Conditions that have been reported in association with BMS include chronic anxiety or depression, various nutritional deficiencies, type 2 diabetes, and changes in salivary function. However, these conditions have not been consistently linked with the syndrome, and their treatment has had little impact on BMS symptoms. Recent studies have pointed to dysfunction of several cranial nerves associated with taste sensation as a possible cause of BMS. Given in low dosages,...

Summary This article on pharmacologic treatments for temporomandibular disorders is from a special supplement issue on the NIH Technology Assessment Conference on the management of temporomandibular disorders (TMDs), held in April 1996. The author notes that drugs are widely used in the management of acute and chronic orofacial pain. Whereas the use of analgesics for acute orofacial pain is well documented, the use of a broad spectrum of drugs for chronic pain is based on few studies. In the absence of data supporting a therapeutic benefit for a drug used chronically for pain, toxicity associated with the drug can still occur. It is critical, therefore, to assess the balance between therapeutic benefit and safety. The author reviews current evidence supporting the use of several drug classes for TMD and identifies therapeutic controversies in need of further research. Drug classes discussed include nonopioid analgesics, opioids, corticosteroids, antidepressants, benzodiazepines, and...

Summary This article on the pharmacologic management of myofascial pain and dysfunction is from an issue of Oral and Maxillofacial Clinics on the medical management of temporomandibular disorders (TMD). The authors discuss the most frequently used classes of drugs, providing information about their mechanism of action, indications and contraindications, methods of use, and possible adverse side effects. Specific drugs discussed include anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, and corticosteroids muscle relaxants (other than benzodiazepines) antianxiety medications antidepressant medication opiate narcotic analgesics and local anesthetics. A final section covers the placebo effect. The author emphasizes the importance of understanding the patient in terms of compliance and tolerance of side effects in order to achieve successful management with pharmacologic therapy. 2 figures. 6 tables. 25 references. (AA-M).

Summary This article presents a panel discussion on the role of the physician in the treatment of Alzheimer's, including handling the patient's response to the diagnosis, managing behavioral aspects of the illness, treatment of depression and other emotional symptoms, treatment of other medical conditions, and helping patients live with cognitive impairment. The panelists also considered such drug therapy as THA, Hydergine neuroleptics for agitation, and benzodiazepines for sleep disorders.

Summary This article provides an overview of burning mouth syndrome (BMS), a chronic oral-facial pain condition that affects many U.S. adults. The authors provide an update on what is known about the epidemiology, etiology, and treatment of BMS. Specific topics include the clinical presentation of BMS statistics on the incidence and prevalence of BMS oral disorders that can result in BMS, such as denture allergy, salivary dysfunction, or taste disturbances systemic conditions that can result in BMS, such as hematological disorders, nutritional disorders, anemias, central nervous system disorders, psychological disorders, diabetes mellitus, or Sjogren's syndrome and treatment options, including the use of antidepressants and benzodiazepines. The authors conclude that the dental profession should formulate standardized symptom and diagnostic criteria so that multidisciplinary investigations can identify effective and reliable treatment strategies. 2 figures. 2 tables. 65 references....

Summary This article reviews the literature on alternatives to neuroleptics in the treatment of the agitated patient with progressive dementia. Specific neuroleptics discussed are the following serotoninergic agents (trazodone), azapirones (buspirone), benzodiazepines, beta-blockers, anticonvulsants, and lithium. The authors state that, although a variety of potential alternatives to the neuroleptics in the management of

Summary This article reviews the pharmacologic management of the psychotic patient, to familiarize oral and maxillofacial surgeons with the care of these patients. The author notes that the trend to outpatient care extends to the psychiatric patient and more health care providers will be faced with the care of this patient population. The author reviews potential drug interactions and clinical considerations for patients already under maintenance therapy. The article covers antipsychotic agents, mood disorders, HCAs (including tricyclic drugs), MAOIs (derivatives of hydrazine or amphetamine), SSRIs (antidepressants), bipolar disorder, and antianxiety agents, specifically benzodiazepines, barbiturates, and buspirone. The emphasis in each section is on pharmacodynamics, drug interactions, and anesthetic concerns. 3 tables. 25 references.

Summary This article reviews the phenomenology of agitation and its pharmacologic treatment in patients with dementia, including the use of benzodiazepines, neuroleptics, beta-adrenergic-blocking agents, serotonergic agents, carbamazepine, and lithium. Persistent and acute agitation may be treated through sedation with neuroleptics or benzodiazepines. However, care should be taken to not maintain patients on these medications for protracted period of time, i.e., beyond 4 to 6 weeks. For chronic agitation, the severe side effects and limited efficacy of neuroleptics and benzodiazepines diminish their usefulness. The authors recommend a trial of the serotonergic agents, including buspirone, trazodone, and serotonin selective reuptake inhibitor antidepressants, as first-line treatment for chronic agitation in patients with dementia. Second-line treatment includes beta-blockers, carbamazepine and lithium when agitation is associated with manic affects. The authors suggests the usage of...

Determined by neuroradiologic, electroencephalographic, and neuropsychological testing. The author suggests that proposed strategy is an empirical one that has not been validated through appropriate scientific study, but has been used clinically. The treatment strategy for acute agitation usually depends on antipsychotics for psychotic behaviors and benzodiazepines for nonpsychotic behavior. For chronic psychotic agitation, the strategy suggests use of neuroleptics as a first step, with appropriate drugs added according to patient response. The strategy for chronic nonpsychotic agitation calls for the treatment of specific psychiatric syndromes and neural dysfunctions, with specific suggestions for drug types for use in neural dysfunction. Symptoms other than agitation that may be amenable to a pharmacologic approach are emotional lability, abulia, sleep disturbances, decreased food intake, and inappropriate sexual behavior. 52 references.

Summary This journal article describes guidelines for prescribing psychoactive drugs in the elderly. Primary care physicians are usually the first to see elderly patients with emotional problems secondary to dementia and other psychiatric disorders. Because these problems often can be treated effectively, physicians should have a working knowledge of the guidelines for optimal use of psychoactive medications. This article provides an up-to-date compendium of prescribing information on benzodiazepines and antidepressants for use by primary care physicians in treating elderly patients with cognitive or behavioral dysfunction. Included is practical information on the half-life of drugs, time to steady state, and other data geriatricians need for effective prescribing and dosing.

Summary This journal article describes the effects of a daily program of diverse activities on the disturbed behavior of three patients with severe dementia, aged 76, 81, and 82 years. The patients were on a Dutch psychogeriatric ward and had severe disturbed behavior that had not responded to benzodiazepines or antipsychotic drugs. The Behavioral Rating Scale for Psychogeriatric Inpatients, Social Dysfunction and Aggression Scale, and Clinical Global Impression Improvement Scale were used to assess behavior during baseline, intervention, and followup periods of 4 weeks each. During the intervention period, the patients participated in a twice-daily program of various group, musical, physical, and social activities off the ward. During baseline and followup, they followed the regular ward activities. The patients had different responses to the intervention. One patient worsened during intervention but improved during followup. The second patient improved on global functioning during...

Summary This journal article discusses pharmacologic approaches to the management of Alzheimer's disease (AD) and some of its symptoms. The first section discusses treatment strategies using various types of cholinergic drugs, including acetylcholine (ACh) precursors, cholinesterase inhibitors, a combination of ACh precursors and cholinesterase inhibitors, cholinergic agonists, and indirect enhancement of cholinergic activity in the brain. The next three sections address the use of antiinflammatory agents, antiamyloidogenic and antioxidant therapy, and estrogen replacement therapy to prevent or delay the onset of AD. The fifth section examines the management of psychosis and agitation in AD with such medications as antipsychotics, benzodiazepines, trazodone, buspirone, anticonvulsants, beta-adrenergic blockers, lithium, and selective serotonin reuptake inhibitors. Finally, the article discusses the use of selected antidepressant medications for the management of depressive symptoms in...

Anticholinergics, anti-inflammatory agents, antibiotics). Researchers found that cognitive side effects may be produced by a variety of medications from multiple drug classes. The most commonly implicated drugs are the anticholinergics, benzodiazepines, narcotics, neuroleptics, and sedative-hypnotics. The authors discuss the specific cognitive problems that these drugs may produce. 131 references.

Summary This journal article for health professionals reviews current knowledge about sleep disorders in patients with fibromyalgia and the treatment strategies currently used. Sleep disturbance may be central to the fibromyalgia syndrome. Many patients have difficulty in falling and staying asleep and awaken unrefreshed with intensified morning aching. Alpha-delta sleep, in which internally triggered arousal results in delta sleep deprivation, appears responsible. Moreover, such triggers may also lead to depressed and anxious mood, fatigue, morning stiffness, and musculoskeletal pain, which, in turn, contribute to the nonrestorative sleep cycle. Success in improving sleep is greatest when general approaches and specific sleep interventions are combined. Psychotherapy, behavioral therapy, and exercise may lead to better sleep habits and symptomatic relief. Tricyclic agents improve sleep and overall functioning. Benzodiazepines administered with nonsteroidal anti-inflammatory drugs may...

Summary This journal article reviews selected drug treatments for psychiatric symptoms and behavioral disturbances in dementia. Several different classes of drugs have been used in the treatment of behavioral disorders in dementia neuroleptics, anticonvulsants, antidepressants, beta-blockers, and benzodiazepines. Neuroleptics are the drugs of first choice for treating behavioral disorders, and they generally are considered to be moderately effective. These drugs are known to improve anxiety and mood and reduce aggression, agitation, hostility, and uncooperativeness. Anticonvulsants such as carbamazepine and sodium valproate also may be effective in

Summary This journal article reviews the Literature on antipsychotic treatment in patients with behavioral disturbances of dementia. First, it reviews results from the four randomized, double-blind, placebo-controlled trials of neuroleptics in dementia which were published in the past 20 years. Then it summarizes findings concerning the efficacy and safety of clozapine, risperidone, and benzodiazepines. Next, the article discusses the optimal dose of haloperidol, the optimal duration of antipsychotic treatment, and antipsychotic side effects. In 1 study of the course of psychopathology, conducted by the author and colleagues, 235 patients with early, probable Alzheimer's disease (AD) were followed at 6-month intervals for up to 5 years. Agitation was found to be the most persistent symptom, which suggests that prolonged treatment may be needed. Finally, the article suggests an approach to initiating and monitoring antipsychotic treatment in older patients with dementia. In the...

Summary This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents anticonvulsant agents (carbamazepine and valproic acid) anxiolytic agents (benzodiazepines and buspirone) antidepressants (trazodone and selegiline) serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline) cholinergic therapy and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4...

That will significantly increase synthetic versatility. Applications will include both nucleophilic and electrophilic C-O bond cleavage of 4 with N-O bond retention, in both intermolecular and intramolecular processes N-O bond cleavage to give substituted carbocycles 5 and C C bond reactions to give 6 and other intermediates. Products from these reactions will be used to prepare focused sets of targets, including novel 5-lipoxygenase inhibitors, neuraminidase inhibitors, benzodiazepines, diazepines, carbocyclic nucleosides and analogs (aristeromycin, carbavir, abacavir, stavudine, carbocyclic oxanosine, and their nor analogs, carbocyclic forms of polyoxins, sinefungin, nucleoside Q, puromycin and analogs), novel phosphodiesterase inhibitors, streptazolin, novel oxazolidinone antibiotics, diketopiperazines (tryprostatin analogs), novel amino acids and peptides related to bacterial diaminopimelic acids (DAP) as well as new amino acids and peptides that represent the first of a novel...

Summary (Verbatim from the Applicant's Abstract) While most partial and generalized seizures are relatively brief in duration, during some seizures, early termination fails and a prolonged epileptic state occurs that has been termed status epilepticus. Status epilepticus is relatively common, has a high morbidity and mortality and is a medical emergency requiring immediate treatment. Spontaneous seizure termination may involve activation of gamma-aminobutyric acid (GABA) receptor (GABAR)-mediated inhibition. If the GABAergic inhibition fails to terminate the seizure, a progressive reduction of GABAR-mediated inhibition develops that, when severe enough, results in a prolonged seizure. Status epilepticus in humans is treated acutely with benzodiazepines as well as barbiturates, which enhance GABAR-mediated inhibition. However, benzodiazepines are often efficacious early but not late in status epilepticus. We have shown that properties of dentate granule cell GABAR are altered during...

Summary Benzodiazepines (BZs) are useful clinically, however tolerance to many of their actions occurs with prolonged administration. Investigations of GABA-A receptors (GABARs) in rats chronically treated with flurazepam have shown significant decreases of inhibitory function in hippocampus and have uncovered changes in excitatory amino acid receptor (EAAR)-mediated activity. Preliminary studies of NMDA and AMPA receptors detected changes in subunit mRNA and protein, consistent with the hypothesis that impaired GABAR-mediated inhibition leads to compensatory changes in EAARs. Electrophysiological studies suggest that functional EAAR-mediated transmission may be altered affecting synaptic plasticity as well. From these findings, three hypotheses were developed and will be tested by 3 Specific Aims 1) is to characterize changes in NMDA and AMPA receptor protein and receptor number using i) quantitative immunohistochemistry, ii) Western analysis and iii) autoradiographic binding studies...

Summary This journal article discusses a case study of delirium, complicated by preexisting dementia, that was resolved rapidly following initiation of the cholinesterase inhibitor donepezil. The authors suggest that cholinergic dysfunction may have played a role in the etiology of the patient's delirium. Delirium is a common complication of dementia that may produce agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. Delirium may also produce considerable morbidity. Delirium is not always reversible and there is no specific treatment for persistent delirium the main treatment approach is to treat the underlying medical problem. The authors state that future research needs to be directed at the issue of cholinergic activity in delirium through monitoring serum anticholinergic activity and its response to procholinergic therapy. 17 references. (AA-M).

Summary Emerging results from clinical and basic research indicate that persistent pain results in changes in the central nervous system. This article reviews data that support the use of tricyclic antidepressants for neurogenic or atypical pain, and benzodiazepines for musculoskeletal pain. Other topics covered include the pathophysiology of persistent pain and the pharmacological management of temporomandibular disorders (TMDs) with antidepressants, benzodiazepines, muscle relaxants, non-opioid analgesics, corticosteroids, and opioids. The authors stress that dentists must weigh the benefits of the chronic administration of a drug for the management of TMDs against the equivocal scientific support for the use of many drug

Summary This article presents current perspectives on drug therapies for anorexia nervosa and bulimia nervosa. Topics include diagnostic considerations, drug treatment for anorexia nervosa, and drug treatment for bulimia nervosa. The authors maintain that there is little if any role for pharmacotherapy in anorexia nervosa. Drugs used to promote food intake and weight gain in bulimia nervosa have provided disappointing results. Newer antidepressants, anticonvulsants, benzodiazepines, lithium, fenfluramine, and opiate antagonists may prove useful, although all require further research. 1 table. 85 references.

Summary This is a proposal for a Mentored Clinical Scientist Development Award to provide supervised experience in clinical research, didactic education, and some clinical activities. This will provide a foundation for a career in academic medicine with opportunities for research, teaching, and some clinical practice. This award will allow the candidate to begin research in substance abuse treatment and Health Services Research (HSR) in a supervised setting. The effects of symptom-triggered therapy versus scheduled dosing for acute withdrawal from alcohol will be studied in a general medical population. The first two years of the award period will be spent taking graduate courses in biostatistics, pharmacology, research design and methodology, attending seminars on HSR topics, and refining the final study protocol by doing a pilot study. Practical clinical experience will be gained in outpatient clinics including rotation through community programs such as a local methadone...

Summary This journal article summarizes Federal guidelines for benzodiazepine and antipsychotic drug use in long-term care residents with dementia. The Nursing Home Reform Amendments of the Omnibus Budget Reconciliation Act of 1987 (OBRA 87) have resulted in close supervision of the use of unnecessary drugs for residents in Medicare and Medicaid certified nursing homes. They require documenting the behavioral indication for psychotropic drugs, monitoring their safety and efficacy, drug holidays, behavioral management instead of drugs when possible, and systematic dose reductions unless clinically contraindicated. Long-acting benzodiazepines generally are not recommended for use in older patients. Short-acting benzodiazepines may be used for anxiety, insomnia, and dementia-associated agitated states that represent a danger to the patient or others. Antipsychotics may be used for dementia with psychotic features, continuous crying or screaming that impairs functional status, and...

The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on benzodiazepines. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the...

In March 2001, the National Institutes of Health issued the following warning The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with benzodiazepines is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about benzodiazepines, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where...

In addition to new models, work is being conducted to improve the range of behavioral tests employed in vivo (Figure 1.3). For example, spontaneous exploratory activity assessed in the open field paradigm is classically used as a measure of anxiety-related behavior in rodents.28 This test has been used as a measure of locomotor activity in pain models29 and more recently, additional measures of thigmotactic behavior indicate the presence of altered exploratory behavior in rodent models of pain without the presence of locomotor deficits. This behavior is sensitive to clinically employed analgesics, such as gabapentin and morphine,19,27 suggesting the thigmotaxis to be correlated to a nonstimulus-evoked pain-like behavior in rodents be it spontaneous pain or pain comorbidities.

Sion and anxiety) not only emerge as a consequence of pain but also can contribute to pain, thereby exacerbating and maintaining it. Psychological factors can likewise interfere with treatment adherence and efficacy. Patients' frustration caused by ongoing pain, the effects on functioning, and the impact on families and relationships can contribute significantly to psychiatric morbidity. As a result of these factors, leaders in pain management training declared traditional medical models of pain to be too shortsighted and required a modification in traditional training conceptualizations (Loeser 2001).

Neural correlates of allodynia have been examined in various conditions, including patients with neuropathic pain, central pain, or experimentally provoked allodynia. However, the existing data are controversial with some suggesting that allodynia is processed differently than nociceptive pain and others suggesting they share a common neural basis. Areas shown to be involved in allodynia include the parietal association cortex,194 medial thalamus, putamen, and prefrontal cortex.195 The ACC, which is almost always activated during acute pain in normal subjects and is involved in the affective (cognitive-evaluative) component of pain, has been differentially associated with processing of allodynia.196197, 198,199 This suggests that A-p-mediated pain may have a unique cortical representation in some situations which may aid further understanding of the phenomenon that is tactile allodynia. The amygdala, which plays an important role in fear-conditioning and affective disorders, such as...

From there, we started parallel autoradiographic studies to establish what came to be the 5-HT2C receptor, as will be discussed later in section 1.4 in this chapter. The project in fact followed a research plan carried out in parallel in two different buildings Autoradiographic experiments were done at building 360 (JMP lab), while membrane assays were carried out at building 386 (DH lab). During the autumn of 1983 and the whole year 1984, it become quite usual to Angel to walk daily from one place to the other, bearing tissue samples, autoradiograms and counter prints in his hands, and frequently, a certain level of anxiety in his mind, since we were using old-generation liquid scintillation counters, with rather modest throughput, when we were preparing hundreds of samples. This meant that they had to be loaded and unloaded one by one, by hand with two or three loading sessions per day, weekends included every sample was labeled by hand in case of counter failure and to allow...

Alprazolam is a high-potency, short-acting anxiolytic benzodiazepine medication used in the treatment of anxiety, panic, and phobic disorders. It has some antispas-modic and anticonvulsant effects. It is not antidepressant. It is sometimes used in conjunction with antipsychotic medication in acute psychotic episodes. Unwanted effects include sedation, headaches, paradoxical excitement, confusion, cognitive and psychomotor impairment, and confusion in the elderly. Long-term use may induce dependence with withdrawal reactions. Recreational use and abuse can occur alprazolam is a scheduled substance.

Clonazepam Note Anticonvulsant effects are based on the abolition of THE ++ indicates high potency + indicates moderate potency and - indicates no anticonvulsant activity. Protective index (PI) is defined as the TD50 ED50 (see text). High PI values indicate minimal drug-induced neurological deficit at doses that inhibit THE. The antiepileptic drugs effective in generalized tonic-clonic seizures have the greatest potency and lowest incidence of adverse neurological effects (highest PI) when tested in threshold elec-troshock or threshold for maximal seizures (MEST) in mice. Primidone induces effective anticonvulsant activity only when tested in MEST.69 The benzodiazepines have anticonvulsant activity only at doses that induce neurological deficit in all models. Ethosuximide is effective only in absence seizures and has no activity in the rodent electroshock models. Relative potency and PI values are calculated from the reviews by L scher et al.,7 Krall et al.,6 White et al.,8 L scher...

Estimates of the economic burden associated with pain fail to do justice to the extent of suffering and reduced quality of life experienced by patients and warrants pain relief being regarded as a universal human right.18 Chronic pain, along with musculoskeletal disorders, has been shown to be associated with some of the poorest quality-of-life states.60,61,62,63 In patients referred to a Danish multidisciplinary pain center, the severity of impairment was equal to or lower than patients with cardiopulmonary diseases and major depression, and their Psychological General Well-being Scale scores were lower than those with hypertension and gastrointestinal problems, while they also displayed high levels of anxiety and depression, as measured by the Hospital Anxiety and Depression Scale.63 In a study of over 600 patients attending a chronic pain clinic in Sydney, Australia, there were greatly reduced SF-36 domain scores between clinic patients and Australian norm values, as shown in Table...

Whitlock et al. describe progress in the discovery of SSRIs, noradrenaline reuptake inhibitors (NRIs), and SNRIs from 2000 to the present day. Whilst Chen et al. focus on recent developments in the search for triple SERT, NET and DAT reuptake inhibitors. The interest in these areas stems not only from the potential for improved antidepressant efficacy and side effect profiles, as has been proposed for the triple reuptake inhibitors 38 , but the recognition that by tweaking the transporter profile potential therapies for other diseases associated with neurotransmitter imbalance can be developed. For example, although duloxetine 6 (Fig. 1), a dual SNRI, was initially launched in 2004 for the treatment of major depressive disorder (MDD) 39 , since 2004 additional approvals have been granted for pain associated with diabetic neuropathy 40 and fibromyalgia 41 , for stress urinary incontinence 42 and generalised anxiety disorder 43 . NRIs have been licensed for the treatment of attention...

From the Regulatory side, the FDA in North America (http www.fda.-gov cder guidance 5900dft.doc) and other regulatory bodies, including the MHLW in Japan, have published draft guidelines (for example the FDA's VDGS Voluntary Data Submission Guidelines) to provide guidance to pharmaceutical companies on how pharmacogenetic data will be used as part of regulatory decisions and to encourage the inclusion of pharmacogenetic data as part of drug development. It should be noted that such pharmacogenetic data may be used to support more efficient and successful clinical development strategies, without necessarily resulting in label restrictions based on genotype. Rather, data can be applied to ensure that novel, more effective medicines reach the patient as quickly as possible (Roses 2004). An example of this for psychiatry is the use of pharmacogenetics to dissect out placebo response, or perhaps more correctly, non-specific drug response, a major confounder in clinical studies not only for...

Often times, psychiatric illnesses are associated with health behaviors and pyschophysiologic changes that promote medical illness. Attributing a patient's pain to solely a psychiatric cause is not a diagnosis of exclusion. More importantly, undertreated psychiatric disease may exacerbate pain states (Hudson et al. 1985). Thus, to assess the psychiatric status of the chronic pain patient, a physician should perform a Mini-Mental status exam and discuss any existing depression or anxiety symptoms (Wittink et al. 2004).

Although Parkinson's disease (PD) is classified as a movement disorder, it should also be considered as a neuro-behavioral'' disorder. The diagnosis of PD is based on the presence of clinical criteria having to do purely with movements and the absence of exclusionary or atypical features, laboratory tests being of little or no value. Nevertheless, the most devastating aspects of PD are more often behavioral. Other nonmotor problems, such as sympathetic dysfunction and sleep disorders have only attracted clinical and research attention in the last few years. For perspective two studies, one a large retrospective review in Australia, and the other, a county wide prospective study with formal testing in Norway, both concluded that by the time of death, 80 of PD patients are demented. In addition, at any point in time, somewhere between 30 and 50 are depressed 40 suffer from anxiety 40 with apathy 30 of drug treated patients with visual hallucinations 5-10 of drug treated patients with...

Called neuroleptics, a term still broadly used in medical jargon which is derived from Greek and loosely translated as grasping the nerve.'' This reflects the fact that originally the sedative effects of these drugs were in the foreground of clinical interest. This was also the origin of the American term major tranquilizers. Next to antipsychotic effects, i.e., reducing delusions and hallucinations, most antipsychotics also have sedative properties. Furthermore, they have been shown to reduce negative symptoms, enhance cognitive functions, ameliorate affective symptoms (both manic and depressive) in patients suffering from schizophrenia and, most likely as a secondary effect, improve the quality of life and psychosocial reintegration (Miyamoto et al. 2003). Although most research with antipsychotics has been performed in schizophrenia patients, the therapeutic actions of these drugs extend beyond this diagnosis. Indications include mania, psychotic depression, schizoaffective...

In view of the GABAA enhancing potential of 3ff.-reduced neuroactive steroids, these steroids have been suggested to possess sleep-modulating or -promoting (Mendels and Chernik 1973), anticonvulsant (Frye and Scalise 2000), anxiolytic (Crawley et al. 1986), and neuroprotective (Rupprecht 2003) properties. Finally, it has been postulated that neuroactive steroids may also contribute to psychiatric symptoms sometimes observed during pregnancy and in the postpartum period (Pearson Murphy et al. 2001).

Anxiety has been defined as an emotional state aroused by the perception of threat, which is subjectively experienced as unpleasant. In its full expression, behavioral, autonom-ic endocrine, affective, and cognitive perceptual changes are manifested. Although usually adaptive, leading to harm avoidance, anxiety may turn out to be disruptive, giving rise to different pathologies. In modern psychiatric classifications, such as the Diagnostic and Statistical Manual, 4th edition, revised (DSM-IV-RT) of the American Psychiatric Association, anxiety is considered pathological when excessive, disproportional to the eliciting event, causing significant distress, disrupting interpersonal relationships, and impairing social and occupational functioning. According to the symptomatology and time course of development, anxiety disorders are classified into different nosological categories, such as generalized anxiety disorder (GAD) and panic disorder (PD). The first question one should face while...

The benzodiazepine or warfarin binding sites on the albumin molecule and basic drugs which bind to aracid glycoprotein (Miiller, 1988 Noctor, 1993) (Table 4). Several recent studies have shown that the plasma concentration of aj-acid glycoprotein is lower in individuals from Chinese than Caucasian populations (Kalow and Bertilsson, 1994). Ethnic differences in the enantio-selective plasma protein binding of basic drugs have consequently been reported. For example, the proportion of the pharmacologically important free (S)-propranolol in plasma is higher in Chinese than Caucasian subjects (Zhou et al., 1991), which may in part account for the higher sensitivity of Chinese patients to propranolol (Zhou et al., 1989).

The clinical interview also affords the opportunity to evaluate the patient's beliefs and cognitions about their pain. However, the primary utility of the clinical interview is to formulate a diagnosis in conjunction with the standardized questionnaires. Particular diagnostic categories carefully evaluated for include levels of depression and anxiety, PTSD, and somatization disorders. This facilitates the design of a comprehensive treatment plan, devised together with the patient as well as the rest of the multidisciplinary team.

Adjuvant analgesics are compounds that are not classified as analgesics, but are used clinically for the relief of pain. This class of analgesics contains a wide range of compounds that belong to a variety of chemical families. They are classified according to their use and their mechanisms of action are often not well defined. For example, antidepressants are used to control neuropathic pain, a2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine) potentiate the anti-inflammatory and analgesic effects of COX inhibitors, while corticosteroids block inflammation and may directly modulate the nociceptive action of substance P. Compounds that have been especially beneficial in the treatment of neuropathic and phantom limb pain include local anesthetics (e.g., mexiletine, flecainide), anticonvulsants (gabapentin, carbamazepine, phenytoin, valproate, clonazepam, lamotrigine), GABA agonists, neuroleptics and calcitonin. Other analgesics such as muscle relaxants and benzo-diazepines are...

The long-term increase in pain sensitivity frequently seen following injury or peripheral nerve damage is thought to be due to both alterations in transmission within the spinal cord and to changes in descending controls that run back to the spinal cord from the brainstem. Within this circuit, nocic-eptive information is also relayed to higher centers in the brain via projection neurones. The neuroanatomy of these ascending pain pathways is highly complex, and supraspinal contacts include centers involved with the sensory-discriminative aspects of pain such as the intensity, location and duration of the stimulus as well as centers involved in the affective-cognitive aspects including anxiety, emotion and memory 61 . Importantly, these are the same areas of the brain that modulate descending serotonergic and noradren-ergic inputs from the brainstem that regulate nocic-eptive processing at spinal levels. Thus, a network of spinal and brain circuits can change spinal sensitivity to...

There are other important sites of opioid actions located in the 5HT and noradrenergic nuclei of the brainstem and midbrain, including the raphe nuclei (RVM), the periaqueductal gray matter (PAG) and the locus coeruleus. These areas of the brain are important in sleep, anxiety and fear and explain how these functions interact with and are altered by pain. Opioid receptors in these zones, when activated, alter the level of activity in descending pathways from these zones to the spinal cord that in turn reduces activity of spinal cord neurones. The relative roles of the 5HT receptors in the spinal cord are unknown but the spinal target for noradrenaline (NA) released from descending pathways is a2 receptors which have similar actions and distribution to the opioid receptors. Sedation and hypotension with a2 agonists presently limit their use as analgesics but they are useful veterinary drugs.

In accordance with the structure of the BBB as a double lipid bilayer, classical neuroactive drugs such as benzodiazepines, neuroleptics and tricyclic antidepressive agents, are all small lipophilic molecules. These small molecular weight neuropharmaceuticals were selected by a trial and error approach because their structural characteristics allow for diffusion-mediated, passive penetration through the BBB.

A recent example of an integrated pharmacological approach to drug discovery is that of the novel anxiolytic AC-5216 (Kita et al., 2004). This compound was synthesized as a potent (Ki 0.3 nM), orally active agonist for the peripheral BZ receptor. Also known as the mitochondrial BZ receptor or translocator protein, this site is involved in the synthesis of endogenous neurosteroids that enhance GABAergic neurotransmission. Whole animal testing revealed that AC-5216 had anti-anxiety effects in mice in the Vogel-conflict test (0.1-3 mg kg p.o.), the light dark box (0.003-0.01 mg kg p.o.), and social interaction tests (0.01-0.3 mg kg p.o.). These actions were blocked by the peripheral BZ mitochondrial BZ receptor antagonist, PK 11195 (3 mg kg i.p.). Further behavioral tests revealed that AC-5216 was also active in the Porsolt forced swim test (3-30 mg kg p.o.), a measure of antidepressant activity. Unlike the classical BZ, diazepam, AC-5216 did not produce muscle relaxation, nor did it...

Painful physical symptoms are also common complaints in depression (194). This may in part be related to the shared 5-HT and NE pathways in depression and pain (195) since 5-HT and NE modulate pain through the descending pain pathways. Serotonergic projections descend through the rostral ventral medulla and the pontine raphe into the spinal cord where they modulate pain. Norepinephrine neurons also project through the dorsolateral pons, locus coeruleus, medial and lateral parabrachial nuclei, and associated areas into the spinal cord to modulate pain. The effects of 5-HT and NE are synergistic in this system. Thus, dual reuptake inhibitors are effective in relieving the physical symptoms associated with depression (196). Recent functional imaging studies indicate that the presence of anxiety may accentuate pain perception (197).

Tasks that could examine these behavioral symptoms in rodents have been already developed and are summarized in Table 1. However, an animal model of autism based solely on behavioral assays would be incomplete. Animal model should also address a combination of the neuro-pathological, biochemical and genetic factors implicated in autism. Another challenge lies in the fact that many clinical hallmarks of autism are difficult or almost impossible to replicate in rodents, e.g., theory of mind (ability to intuit the feelings and intentions of others) or speech deficits. It is also important to realize that assumed core psychopathological phenomena observed in autism are present as common clinical features in schizophrenia, depression, obsessive-compulsive disorder and other medical and psychiatric illnesses. What is specific for autism is a pattern of socio-behavioral aberrations and their appearance before the age of three, and animal models should try to address this fact.

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.